Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of polycarbonate plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers and baby bottles, there is a wide human exposure to this compound. We have demonstrated for the first time that low-dose BPA treatment of gonadectomized female and male rats and monkeys inhibits the synaptogenic effect of sex steroids in the hippocampus and prefrontal cortex. Mounting evidence indicates that remodeling of hippocampal and prefrontal spine synapses is a morphological basis for learning and memory, suggesting that the negative synaptogenic effects of BPA are associated with impaired cognitive performance. According to the National Toxicology Program, available evidence provides a basis for concern, yet the Food and Drug Administration (FDA) concludes that data collected so far is not sufficient to resolve the problem whether BPA exposure represents a threat to human health. The FDA calls for further studies on BPA that are more relevant to human health. In this application, we propose three specific aims that are designed along guidelines published in the most recent FDA report on BPA. Using our established nonhuman primate model, we will test the hypothesis that BPA- induced loss of hippocampal and prefrontal spine synapses and compromised dopaminergic neurotransmission are associated with impaired cognitive performance. In addition, we will analyze whether the effects of BPA are cumulative and whether they are reversible. Finally, infants and children in particular seem to be at the highest level of risk from BPA exposure, because low- dose BPA interferes with neuronal development in rodents, leading to potentially irreversible alterations in behavior. Our last specific aim is designed to address this problem by analyzing whether perinatal BPA exposure causes irreversible harm in our nonhuman primate model. These studies will provide information on the risks of BPA exposure with most relevance to human health, which will be highly valuable for governing bodies to appropriately regulate the use of BPA. PUBLIC HEALTH RELEVANCE: Recent rodent studies suggest that the xenoestrogen, bisphenol A, at levels found in the environment, is capable of diminishing one's ability to learn and interferes with brain development. Because there are considerable differences between the brains of rodents and humans, this suggestion is intensively debated. Therefore, we will investigate how bisphenol A affects the brain and learning capability of adult and juvenile monkeys, to provide results that are more relevant to human health and may guide future environmental policy about bisphenol A.